Throughout this application, various publications are referenced by author and date within the text. Full citations for these publications may be found listed alphabetically at the end of the specification immediately following the Sequence Listing and before the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
Ischemic heart disease is a leading cause of morbidity and mortality in the general population, but especially in patients with diabetes. The prevalence of coronary artery disease is as high as 55% in adult patients with diabetes (Robertson and Strong, 1968). Indeed, data from the Framingham Heart Study demonstrate that mortality from cardiovascular disease in non-insulin dependent diabetes (NIDDM) is more that doubled in diabetic men and more than quadrupled in diabetic women when compared to nondiabetic control subjects (Kannel and McGee, 1979). In addition to increased prevalence, studies have shown that atherosclerosis in diabetic patients is clearly more accelerated and extensive. In one autopsy series, for example, patients with diabetes were found to have more severe disease of the left anterior descending coronary artery (Waller et al., 1980), a higher incidence of two and three-vessel disease (Crall and Roberts, 1978), and a greater diffuseness of distribution of atherosclerotic lesions (Hamby et al., 1976). The findings were confirmed by coronary angioplasty in symptomatic patients (Pyorala et al., 1978).
The reasons for accelerated atherosclerosis in the setting of diabetes are numerous. However, even after correction for dyslipidemia, hypertension and obesity, multivariate analysis studies have indicated that diabetic patients have an excess risk of cardiovascular disease relative to nondiabetic subjects (Kannel and McGee, 1979). For example, in the Nurses' Health Study of 1,500 diabetic subjects among a total of 115,000 women, the incidence of cardiovascular disease was 5-fold higher in the diabetic subjects regardless of their levels of cholesterol (Manson et al., 1991). The data suggest that factors unique to the diabetic population play an important role.